Key Laboratory of Intensive Care Rehabilitation of Shandong, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China; Department of Anesthesiology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China.
Key Laboratory of Intensive Care Rehabilitation of Shandong, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250031, China.
Biomed Pharmacother. 2023 Sep;165:115237. doi: 10.1016/j.biopha.2023.115237. Epub 2023 Jul 27.
Mechanical ventilation (MV) may negatively affect the lungs and cause the release of inflammatory mediators, resulting in extra-pulmonary organ dysfunction. Studies have revealed systemically elevated levels of proinflammatory cytokines in animal models of ventilator-induced lung injury (VILI); however, whether these cytokines have an effect on gut injury and the mechanisms involved remain unknown. In this study, VILI was generated in mice with high tidal volume mechanical ventilation (20 ml/kg). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations in serum and gut measured by ELISA showed significant elevation in the VILI mice. Significant increases in gut injury and PANoptosis were observed in the VILI mice, which were positively correlated with the serum levels of TNF-α, IL-1β, and IL-6. The VILI mice displayed intestinal barrier defects, decreased expressions of occludin and zonula occludin-1 (ZO-1), and increased expression of claudin-2 and the activation of myosin light chain (MLC). Importantly, intratracheal administration of Imp7 siRNA nanoparticle effectively inhibited cytokines production and protected mice from VILI-induced gut injury. These data provide evidence of systemic cytokines contributing to gut injury following VILI and highlight the possibility of targeting cytokines inhibition via Imp7 siRNA nanoparticle as a potential therapeutic intervention for alleviating gut injury following VILI.
机械通气（MV）可能会对肺部造成负面影响，并导致炎症介质的释放，从而导致肺外器官功能障碍。研究表明，在呼吸机诱导的肺损伤（VILI）的动物模型中，促炎细胞因子在全身水平升高；然而，这些细胞因子是否对肠道损伤有影响以及涉及的机制尚不清楚。在这项研究中，通过大潮气量机械通气（20ml/kg）在小鼠中产生了 VILI。ELISA 法测定血清和肠道中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和 IL-6 的浓度显示，VILI 小鼠的浓度显著升高。VILI 小鼠的肠道损伤和 PANoptosis 明显增加，与 TNF-α、IL-1β 和 IL-6 的血清水平呈正相关。VILI 小鼠表现出肠道屏障缺陷，occludin 和 zonula occludin-1（ZO-1）的表达减少，claudin-2 的表达增加，肌球蛋白轻链（MLC）的激活增加。重要的是，气管内给予 Imp7 siRNA 纳米颗粒可有效抑制细胞因子的产生，并保护小鼠免受 VILI 诱导的肠道损伤。这些数据提供了全身细胞因子有助于 VILI 后肠道损伤的证据，并强调了通过 Imp7 siRNA 纳米颗粒靶向细胞因子抑制作为缓解 VILI 后肠道损伤的潜在治疗干预的可能性。
